Cytarabine Ocfosfate, a New Oral Ara-C Analogue, in the Treatment of Acute Leukemia and Myelodysplastic Syndromes

Abstract

Cytarabine ocfosfate (1-β-D-arabinofuranosylcytosine-5′-stearyl-phosphate, YNK-01) is a prodrug of Ara-C, and is slowly converted to Ara-C in the liver, releasing Ara-C into the blood over a prolonged period. It is resistant to both cytidine deaminase and phosphodiesterase. Its activity does not depend on the administration schedule and route, and unlike Ara-C, single administration is as effective as daily administration. YNK-01 is the first commercially available oral derivative of Ara-C in Japan. Phase I studies by single or 5-day consecutive oral administration revealed dose-dependent plasma levels of Ara-C, and the dose-limiting toxicities were thrombocytopenia and gastrointestinal side effects. Five daily oral administrations of 100 mg of YNK-01 gave continuous plasma Ara-C levels at around 1 ng/ml on day 1, and 2 to 4 ng/ml on day 5, plasma Ara-C was detected up to day 7. A phase II study with oral daily administration of 100–450 mg resulted in 2 CR (3%) and 10 PR (18%) in 58 evaluable patients with previously-treated AML, acute leukemia from MDS, CML-BC, hypoplastic acute leukemia or ALL, and 2 CR (4%), 6 GR (13%) and 5 PR (11%) in 45 evaluable patients with RAEB, RAEB-T and CMMoL. Major toxic effects were myelosuppression and gastrointestinal toxicity, including anorexia (35%), nausea/vomiting (19%), diarrhea (9%), malaise (18%), and elevation of GOT/GPT (9%), LDH (6%) and ALP (4%).

In spite of such disadvantages as unpredictable absorption due to nausea/vomiting) this newly developed orally administrable Ara-C analogue will be useful for leukemia, to which low-dose Ara-C is indicated) such as MDS and acute leukemia in elderly patients.